Process for the preparation of 5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines

ABSTRACT

5-Substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines are manufactured from 2-substituted-4-amino-5-methoxypyrimidines in a process that avoids hydrazine and cyanogen halide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/347,968 filed May 25, 2010.

BACKGROUND OF THE INVENTION

The present invention concerns a process for the preparation of5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines.

U.S. Pat. No. 6,005,108 describes certain substituted5,8-disubstituted-[1,2,4]-triazolo[1,5-c]pyrimidin-2-amine compounds andtheir use as intermediates for the preparation of sulfonamideherbicides. 5,8-Dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine is auseful intermediate for the preparation of penoxsulam. Monatsh. Chem.1983, 114, 789 describes the preparation of certain(amino)carbonothioylcarbamates followed by their reaction withhydroxylamine and subsequent cyclization to[1,2,4]triazolo[1,5-a]-pyrimidin-2-amines. WO 2009/047514 A1 describesthe preparation of certain (amino)-carbonothioylcarbamates followed bytheir reaction with hydroxylamine and subsequent cyclization to[1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidinecompounds. U.S. Pat. No. 6,559,101 B2 describes the preparation ofcertain (amino)carbonothioylcarbamates followed by their reaction withhydroxylamine and subsequent cyclization to pyrimidine substituted[1,2,4]triazolo[1,5-a]pyrimidin-2-amines.

5,8-Dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine is produced from2,4-dichloro-5-methoxypyrimidine in a multistep process that involvesboth hydrazine and a cyanogen halide. Hydrazine presents a severeexplosion hazard and is toxic by ingestion, inhalation and skinadsorption. It is classified as a carcinogen and has a TLV of 0.1 ppm inair. Cyanogen halides are highly irritating and very poisonous. It wouldbe advantageous to produce5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-aminesefficiently and in high yield by a manufacturing process that avoidshydrazine and cyanogen halide.

SUMMARY OF THE INVENTION

The present invention concerns the preparation of5-substituted-8-alkoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amines from2-substituted-4-amino-5-methoxy-pyrimidines. More particularly, thepresent invention concerns a process for the preparation of5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines of theformula (I),

in which

X represents halogen or OR; and

R represents C₁-C₄ alkyl;

which comprises:

i) contacting a 2-substituted-4-amino-5-alkoxypyrimidine of the formula

in which X and R are as previously defined

with an isothiocyanatidocarbonate of the formula

in which R is as previously defined,

in a polar aprotic solvent to provide a(pyrimidinylamino)carbonothioylcarbamate of the formula

in which X and R are as previously defined;

-   -   ii) contacting the (pyrimidinylamino)carbonothioylcarbamate with        hydroxylamine in the presence of a base to provide a        (pyrimidinylamino)hydroxy-imino)methylcarbamate of the formula

in which X and R are as previously defined; and

-   -   iii) cyclizing the        (pyrimidinylamino)hydroxyimino)methylcarbamate by heating in an        inert solvent to provide the        5-substituted-8-alkoxy-[1,2,4]triazolo[1,5-c]-pyrimidin-2-amine.

In another embodiment of the invention,5-halo-8-alkoxy[1,2,4]triazolo[1,5-c]-pyrimidin-2-amines can beconverted into the corresponding5,8-dialkoxy[1,2,4]triazolo-[1,5-c]pyrimidin-2-amines by displacement ofthe halogen by an alkali metal alkoxide in an alcoholic solvent.

Another embodiment of the invention comprises a(pyrimidinylamino)carbono-thioylcarbamate of the formula

in which

X represents halogen or OR; and

R represents C₁-C₄ alkyl.

A further embodiment of the invention comprises a(pyrimidinylamino)-hydroxyimino)methylcarbamate of the formula

in which

X represents halogen or OR; and

R represents C₁-C₄ alkyl.

The material may exist as a pair of geometric isomers (E and Z), as wellas in various tautomeric forms.

A further embodiment of the invention comprises a5-halo-8-alkoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amines of the formula

in which

X represents halogen; and

R represents C₁-C₄ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The term alkyl and derivative terms such as alkoxy, as used herein referto straight chain or branched chain groups. Typical alkyl groups aremethyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl and1-methylpropyl. Methyl and ethyl are often preferred. The term halogen,as used herein, refers to fluorine, chlorine, bromine and iodine. Achloro group is often preferred.

The 2-substituted-4-amino-5-alkoxypyrimidine and the alkylisothio-cyanatidocarbonate starting materials are known compounds or canbe prepared by procedures well known to those of ordinary skill in theart.

The present invention concerns the preparation of5-substituted-8-alkoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amines from2-substituted-4-amino-5-methoxy-pyrimidines.

The first step of the present invention (a) concerns the conversion of a4-aminopyrimidine in which

X represents halogen or OR and

R represents C₁-C₄ alkyl

to a (pyrimidinylamino)carbonothioylcarbamate. This is accomplishedusing at least one equivalent and preferably an excess ofisothiocyanatidocarbonate in a polar aprotic solvent, preferablyacetonitrile or ethyl acetate. It is also possible to perform thereaction in the presence of additional diluents, provided those diluentsdo not interfere with the desired reaction and are chemically inert tothe reactants. The isothiocyanatidocarbonate is added at a temperaturefrom 0° C. to room temperature; the mixture is generally heated to sometemperature between room temperature and reflux of the diluent added,preferably to reflux. The product is isolated by conventionaltechniques, such as by filtration of a precipitated or crystallizedmaterial.

In a typical reaction, the aminopyrimidine is dissolved or suspended inethyl acetate and then treated with the appropriate amount of theisothiocyanatidocarbonate. After heating to reflux, the reaction mixtureis cooled to a temperature at which the desired compound precipitatesand is collected by filtration and dried. Optionally, some or most ofthe solvent may be removed by distillation prior to filtration toimprove crystal filtration or reduce solubility of the product in thesolvent and thereby improve recovery.

The second step of the present invention (b) concerns the conversion ofthe (pyrimidinylamino)carbonothioylcarbamate to its(pyrimidinylamino)hydroxyimino)-methylcarbamate equivalent. This isaccomplished using at least an equivalent of hydroxylamine, preferablyas a salt, and a base, such as sodium or potassium carbonate, sodium orpotassium hydroxide or a trialkylamine. Sodium carbonate or sodiumhydroxide are the preferred auxiliary bases. It is not uncommon to useup to 4 equivalents of hydroxylamine and base in this reaction. Thereaction mixture is diluted with water and a polar solvent, preferablyethyl acetate or acetonitrile and is stirred at a temperature between 0°C. and 35° C., preferably at room temperature. It is also possible toperform the reaction in the presence of additional diluents, providedthose diluents do not interfere with the desired reaction and arechemically inert to the reactants. The product is optionally cooled andis isolated by conventional techniques, such as collection by filtrationand drying or flash-chromatography. The material may exist as an E/Zisomeric mixture and/or in various tautomeric forms. Optionally, ratherthan isolating the (pyrimidinylamino)hydroxyimino)methylcarbamate, thereaction may be retained as the reaction mixture and heated to effectthe cyclization to the5-substituted-8-alkoxy[1,2,4]-triazolo[1,5-c]pyrimidin-2-amines andisolated according to the details below.

In a typical reaction, the (pyrimidinylamino)carbonothioylcarbamate,hydroxylamine and base are dissolved in water and either acetonitrile orethyl acetate. The reaction mixture is stirred at room temperature andthen is either heated to convert to the5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, orfiltered and recrystallized from acetonitrile, to isolate the(pyrimidinylamino)hydroxyimino)methylcarbamate. Optionally, some or mostof the solvent may be removed by distillation prior to filtration toimprove crystal filtration or reduce solubility of the product in thesolvent and thereby improve recovery.

The third step of this invention (c) concerns the conversion of theoptionally isolated (pyrimidinylamino)hydroxyimino)methylcarbamate tothe 5-substituted-8-alkoxy[1,2,4]-triazolo[1,5-c]pyrimidin-2-amine usingheat and an inert solvent. It is often preferable to convert the(pyrimidinylamino)hydroxyimino)methylcarbamate to the5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine withoutisolation. This conversion is accomplished by heating the reactionmixture. The product is optionally cooled and is isolated byconventional techniques, such as collection by filtration and drying.

Another embodiment of the invention concerns the conversion (d) of the5-halo-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine

in which

X represents halogen; and

R represents C₁-C₄ alkyl

to its alkoxy analog, 5,8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine,using at least one equivalent and preferably an excess of sodium orpotassium methoxide in an alcohol solvent. It is also possible toperform the reaction in the presence of additional diluents, providedthose diluents do not interfere with the desired reaction and arechemically inert to the reactants. The mixture is stirred at sometemperature between 0° C. and 50° C., with room temperature beingpreferred. The product is optionally cooled and is isolated byconventional techniques, such as collection by filtration and drying.

In a typical reaction, the5-chloro-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine is taken up inacetonitrile at room temperature and treated with 25% sodium methoxidein methanol. The resulting slurry is stirred at room temperature forseveral hours and then filtered and dried to afford5-methoxy-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine. Optionally,some or most of the solvent may be removed by distillation prior tofiltration to improve crystal filtration or reduce solubility of theproduct in the solvent and thereby improve recovery.

The following examples are presented to illustrate the invention.

EXAMPLES

All reagents described were obtained commercially and used withoutadditional purification. HPLC analyses were done on a Perkin ElmerSeries 200 instrument with Diode-array ultraviolet detector. A ZorbaxRX-C8 column was used, employing various ratios of acetonitrile-watermodified with 0.1% phosphoric acid as eluant at a flow rate of 1 mL/minand ultraviolet detection at 220 nm. Nuclear magnetic resonance spectrawere obtained on a Bruker AC 300 NMR spectrometer (300 MHz). Massspectral data was obtained using accurate mass electrospray liquidchromatography-mass spectrometry (ESI/LC/MS) in the positive ion (PI)mode and accurate mass electrospray liquid chromatography-massspectrometry-mass spectrometry (ESI/LC/MS/MS).

Example 1 Preparation of Ethyl[(2-chloro-5-methoxypyrimidin-4-yl)amino]-carbonothioylcarbamate (2)

2-Chloro-5-methoxypyrimidin-4-amine (1) (6.4 g, 0.040 mol) was suspendedin ethyl acetate (100 mL) and heated to near reflux. Ethylisothiocyanatidocarbonate (8.9 g, 1.7 eq) was added all at once, and themixture was maintained at reflux for 10 hours. The resulting slurry wascooled to 15° C., and the solid product was isolated by filtration andthe cake washed with fresh ethyl acetate to afford the title compound inseveral crops as a solid (7.8 g, 67%): mp 182° C.; ¹H NMR (DMSO-d₆): δ11.97 (s, 1H), 11.72 (s, 1H), 8.50 (s, 1H), 4.22 (q, 2H), 3.72 (s, 3H),1.17 (t, 3H); ¹³C NMR (DMSO-d₆): δ 177.82, 153.58, 150.00, 149.01,144.26, 142.63, 62.76, 57.56, 14.44; Mass spec (accurate mass): Calcdfor C₉H₁₁ClN₄O₃S: 290.024039; found, 290.0241.

Example 2 Preparation of Ethyl (Z andE)-[(2-chloro-5-methoxypyrimidin-4-yl)-amino](hydroxyimino)methylcarbamate(3)

Hydroxylamine hydrochloride (280 mg, 4 eq) and sodium bicarbonate (335mg, 4 eq) were combined and dissolved in water (6 mL) at roomtemperature. To this was added a suspension of ethyl[(2-chloro-5-methoxypyrimidin-4-yl)amino]carbonothioylcarbamate (2; 290mg, 1.0 mmol) in acetonitrile (15 mL). The resulting slurry was stirredat room temperature for 1 hour, and the solids were then collected byfiltration. Recrystallization from acetonitrile afforded the titlecompound as a light yellow solid (170 mg, 59%): mp 183-184° C. (dec); ¹HNMR (DMSO-d₆) (mixture of isomers) δ 10.77 (s, 0.6H), 10.5 (s, 0.4H),9.48 (s, 0.6H), 9.34 (s, 0.4H), 9.09 (s, 0.4H), 8.40 (s, 0.6H), 8.11(s,0.6H), 8.11(s, 0.6H), 7.95 (s, 0.4H) 4.19-3.89 (m, 5H), 1.17-1.09 (m,3H); ¹³C NMR (DMSO-d₆): δ: 154.4, 154.0, 149.9, 140.2, 140.0, 139.1,138.6, 138.0, 61.2, 60.9, 57.3, 56.5, 14.8, 14.5; Mass spec (accuratemass): Calcd for C₉H₁₂ClN₅O₄ 289.05778; found, 289.0577.

Example 3 Preparation of5-Chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4) WithoutIsolation of (3)

Ethyl [(2-chloro-5-methoxypyrimidin-4-yl)amino]carbonothioylcarbamate(2) (290 mg, 1.0 mmol), hydroxylamine hydrochloride (143 mg, 2 eq), andsodium bicarbonate (170 mg, 2 eq) were combined. Water (5 mL) andacetonitrile (5 mL) were added at room temperature. The resulting slurrywas stirred at room temperature overnight, then treated with 20 drops ofsaturated aqueous sodium carbonate solution. The resulting solution wassparged with nitrogen and cooled, producing the product as a chalkyprecipitate, which was collected by filtration (in two crops), washedwith water, and dried to obtain the title compound as a solid (139 mg,68%): mp 251° C.; ¹H NMR (DMSO-d₆) δ 7.73 (s, 1H), 3.98 (s 3H); 6.63 (s,2H); ¹³C NMR (DMSO-d₆): 166.30, 148.14, 128.91, 124.67, 57.51; Mass spec(accurate mass): Calcd for C₆H₆ClN₅O 199.026087; found, 199.0256.

Example 4 Preparation of5-chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4) WithoutIsolation of (3)

Hydroxylamine hydrochloride (280 mg, 4 eq), and sodium bicarbonate (210mg, 2.5 eq) were combined in water (5 mL) and stirred for 5 minutes.Ethyl [(2-chloro-5-methoxy-pyrimidin-4-yl)amino]carbonothioylcarbamate(2) (290 mg, 1.0 mmol), suspended in t-butanol (15 mL) was added at roomtemperature. The reaction was stirred at room temperature for 5 hours,and then treated with 10 drops of saturated aqueous sodium carbonatesolution. The reaction slurry was then filtered, and the product solidswashed with water and dried to obtain the title compound as a off whitesolid (330 mg, 83%) that was identical in HPLC retention to previouslydescribed 5-chloro-8-methoxy[1,2,4]triazolo-[1,5-c]pyrimidin-2-amine(4).

Example 5 Preparation of5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5)

5-Chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4; 100 mg,0.50 mmol) was suspended in acetonitrile (5 mL) at room temperature andtreated with 25% sodium methoxide in methanol (200 mg, 2 eq). Theresulting slurry was stirred at room temperature for 1.5 hours and thenfiltered. The solids were washed with water and dried to afford thetitle compound as a chalk-colored solid (87 mg, 88%) that was identicalin HPLC retention to authentic5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5): mp 185-186°C.; ¹H NMR (DMSO-d₆) δ 7.48 (s, 1H), 6.38 (br s, 2H), 4.04 (s, 3H), 3.88(s, 3H); EIMS m/z 195.

Example 6 Preparation of Ethyl[(2,5-dimethoxypyrimidin-4-yl)amino]carbono-thioylcarbamate

2,5-Dimethoxypyrimidin-4-amine (6) (3 g, 0.0193 moles) was dissolved in18 g of ethyl acetate. Ethyl isothiocyanatidocarbonate (2.77 g, 0.0208moles) was added in one portion. The solution was heated to 78° C. andheld at that temperature for 11 h. An additional 1.4 g of the ethylisothiocyanatidocarbonate was added and the mixture heated for 2.5 h.The mixture was allowed to cool to 22° C. and filtered. The resultingsolid was washed with ethyl acetate (20 mL) and dried to a constantweight in a fume hood to afford the title compound as a yellow solid(4.81 g, 89%): ¹³C NMR (DMSO-d₆, 100 MHz) δ 177.5, 158.4, 153.3, 149.5,142.3, 139.5, 62.6, 57.6, 55.2, 14.4; HRMS (ESI), calcd for C₁₀H₁₄N₄O₄S,286.0736; found, 286.0727.

Example 7 Hydroxylamine Addition to Produce 8 and Cyclization to Form5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5)

Ethyl [(2,5-dimethoxypyrimidin-4-yl)amino]carbonothioylcarbamate (7;4.30 g, 0.0154 moles) was dispersed in 24 g of ethyl acetate.Hydroxylamine hydrochloride (1.28 g, 0.0193 moles), water (3.84 g), and2M NaOH (12.61 g, 0.0252 moles) were then added to the stirring slurry.The internal temperature rose to 26° C. after the NaOH was added. Ethyl(E/Z)-[(2-chloro-5-methoxy-pyrimidin-4-yl)amino](hydroxyimino)-methylcarbamate(8) was not isolated but was heated to 50° C. to cyclize. The mixturewas cooled to room temperature and allowed to stir overnight. The slurrywas filtered at room temperature and the cake was washed with water (3×8g) and dried to a constant weight in the fume hood providing the titlecompound as a tan solid (3.16 g, 105% yield by weight). The majorcomponent had a retention time identical to authentic5,8-dimethoxy[1,2,4]-triazolo[1,5-c]pyrimidin-2-amine (5). In a separateexperiment ethyl(E/Z)-[(2,5-dimethoxy-pyrimidin-4-yl)amino](hydroxyimino)methylcarbamate(8) was isolated via chromatography on silica gel (chloroform as theeluent) providing a white solid (0.4 g, 13%), which was a ca. 77/23mixture of geometric isomers: ¹H NMR (DMSO-d₆) (mixture of isomers) δ10.65 (s, 1H), 10.34 (s, 0.3H), 9.56 (s, 1H), 8.98 (s, 0.3H), 8.94 (s,0.3H), 8.20 (s, 1H), 8.00 (s, 1H), 7.82 (s, 0.3H), 4.25-3.90 (m, 2.6H),3.88 (s, 3H), 3.81 (s, 0.9H), 3.78 (s, 3H), 3.22 (s, 0.9H), 1.20-1.15(m, 3H); Mass spec (accurate mass): Calcd for C₉H₁₂ClN₅O₄ 289.0578;found, 289.0571.

1. A compound of the formula

in which X represents halogen or OR; and R represents C₁-C₄ alkyl.
 2. Acompound of the formula

in which X represents halogen or OR; and R represents C₁-C₄ alkyl.